Synthesis of Coupling Substrates for Use in a Highly Enantioselec

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Georgia State University Digital Archive @ GSU

Chemistry eses Department of Chemistry

4-4-2012

SYNTHESIS OF COUPLING SUBST TESFOR USE IN A HIGHLY

ENANTIOSELECTIVE CONJUGATEDTRIENE CYCLIZATION ENABLED BY A CHI L N-HETEROCYCLIC CARBENEChristopher A. TothGeorgia State University , [email protected]

is esis is brought to you for free and open access by the Department of Chemistry at Digital Archive @ GSU. It has been accepted for inclusion inChemistry eses by an authorized administrator of Digital Archive @ GSU. For more information, please [email protected].

Recommended CitationToth, Christopher A., "SYNTHESIS OF COUPLING SUBST TES FOR USE IN A HIGHLY ENANTIOSELECTIVECONJUGATED TRIENE CYCLIZATION ENABLED BY A CHI L N-HETEROCYCLIC CARBENE" (2012).Chemistry Teses.Paper 48.h p://digitalarchive.gsu.edu/chemistry_theses/48
http://digitalarchive.gsu.edu/http://digitalarchive.gsu.edu/chemistry_theseshttp://digitalarchive.gsu.edu/chemistrymailto:[email protected]:[email protected]://digitalarchive.gsu.edu/chemistryhttp://digitalarchive.gsu.edu/chemistry_theseshttp://digitalarchive.gsu.edu/


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SYNTHESIS OF COUPLING SUBSTRATES FOR USE IN A HIGHLY ENANTIOSELECTIVE CONJUGATED TRIENE

CYCLIZATION ENABLED BY A CHIRALN-HETEROCYCLIC CARBENE

by

CHRISTOPHER A. TOTH

Under the Direction of Professor Hao Xu

ABSTRACT

The ability to generate chiral building blocks is of paramount importance to organic chemists.

This problem presents itself most notably at the interface of chemistry and biology, where molecules of

only a single enantiomer can induce function to many biological systems. In this context, recent

developments in the field of organocatalysis, most notably the employment of chiral N-heterocyclic

carbenes (NHCs) have shown much promise.

Our group has recently shown that one possible chiral NHC catalyzed Stetter cyclization product

of a conjugated triene, a highly functionalized cyclopentenone, contains both a chiral center and an

adjacent conjugated diene. This structure can be easily elaborated to a bicyclic structural motif present

in some biologically active natural products from the ginkgolide family, and is difficult to access by other

means. The synthesis of novel vinyl stannanes and other coupling substrates involved in the

development of the aforementioned reaction discovery are described in this report.

INDEX WORDS: Asymmetric catalysis, N-heterocyclic carbene, Synthesis, Triene, Enantioselective,

Intramolecular stetter reaction


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SYNTHESIS OF COUPLING SUBSTRATES FOR USE IN A HIGHLY ENANTIOSELECTIVE CONJUGATED

TRIENE CYCLIZATION ENABLED BY A CHIRALN-HETEROCYCLIC CARBENE

by

CHRISTOPHER A. TOTH

A Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of

Master of Science

in the College of Arts and Sciences

Georgia State University

2012


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Copyright byChristopher Alan Toth

2012


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SYNTHESIS OF COUPLING SUBSTRATES FOR USE IN A HIGHLY ENANTIOSELECTIVE CONJUGATED

TRIENE CYCLIZATION ENABLED BY A CHIRALN-HETEROCYCLIC CARBENE

by

CHRISTOPHER A. TOTH

Committee Chair: Hao Xu

Committee: Binghe Wang

Kathy Grant

Electronic Version Approved:

Office of Graduate Studies

College of Arts and Sciences

Georgia State University

May 2012


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DEDICATION

I would like to dedicate this work to my loving father and mother, Glenn and Jean Toth. They

encouraged me to pursue an education in something that I truly enjoy, without this I would not be

where I am today.


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ACKNOWLEDGEMENTS

I would like to first acknowledge Professor Hao Xu, for mentoring me and giving me the

opportunity to work successfully in his laboratory. I would also like to acknowledge Dr. Guansai Liu for

his helpful guidance over the past two years, and Phillip Wilkerson for being an excellent friend and co-

worker.


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TABLE OF CONTENTS

LIST OF FIGURES ............................................... ..................................................... ............... vii

1. INTRODUCTION ...................................................... .................................................... ....... 1

1.1 Carbenes in organocatalysis ............................................... .......................................... 1

1.2 Discovery of a novel asymmetric stetter cyclization ...................................................... 4

1.3 Synthesis of conjugated trienes ................................................... ................................. 6

2. SYNTHESIS OF COUPLING SUBSTRATES .................................... .......................................... 7

2.1 Synthesis of vinyl tins................................................................................................... 7

2.2 Synthesis of vinyl iodides ........................................................................................ ..... 9

3. RESULTS .............................................. ...................................................... ...................... 10

4. CONCLUSIONS .............................................. ..................................................... .............. 11

5. EXPERIMENTAL ............................................................................................................... 11

5.1 General ..................................................................................................................... 11

5.2 Synthesis of vinyl tin compounds ................................................................. .............. 12

5.3 Synthesis of vinyl iodide compounds .................................................... ...................... 12

5.4 Compound Characterization ............................................... ........................................ 12

6. REFERENCES ................................................. ..................................................... .............. 21

7. SPECTRA ......................................................................................................................... 23


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LIST OF FIGURES

Figure 1. Structure of thiamine and its active carbene species .................................................................... 1

Figure 2. First stable crystalline carbene ...................................................................................................... 2

Figure 3. Examples of chiral triazolium carbene precursors ......................................................................... 3

Figure 4. Proposed catalytic cycle ................................................................................................................. 5

Figure 5. Structure of ginkgolide B ................................................................................................................ 6


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1. INTRODUCTION (LITERATURE OVERVIEW)

1.1 Carbenes in Organocatalysis

The demand for catalytic methods to effect efficient chemical transformations cannot be

understated. Catalysis offers reduction in waste and expense via sub-stoichiometric amounts of

reagents. In comparison to the expensive transition metal catalysts pioneered in the early 1970s,

organocatalytic methods have received an enormous amount of attention in recent years. 1 These

methods have been shown to be highly efficient for the carbon-carbon bond formations that play such

an important role in modern organic syntheses. In addition, organocatalyic processes are

environmentally friendly, selective and easy to use. In this context, much effort has been taken to mimic

the seemingly effortless methods by which natural biochemical processes occur. One particularly

pertinent example, the coenzyme thiamine (vitamin B 1), utilizes a nucleophilic carbene as its active

species (Figure 1). 2

Figure 1. Structure of thiamine (left) and a general carbene species (right)

Carbenes are the most investigated reactive species in the field of organic chemistry. 1 These

neutral species contain a bivalent carbon atom with only six valence electrons (Figure 1). As a

consequence of these unique characteristics, many carbenes are highly reactive. Evidence for their

existence was first discovered by Buchner and Curtis in the late 19 th century. 3 It was not until the late


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1980s that Bertrand and co-workers isolated and characterized the first stable carbene. 4 This was

followed closely by Arduengo et al. in their isolation of a kinetically and thermodynamically stable N-

heterocyclic carbene based on the imidazole moiety (Figure 2). 5

Figure 2. First stable crystalline carbene prepared by Arduengo et al.

Even before the isolation of the first persistent carbene, thiazolium salts had been known to

catalyze the condensation of benzaldehyde to benzoin products. 6 The umpolung or polarity reversed

reactivity of aldehydes promoted by a carbene intermediate was proposed by Breslow in 1958. 7

Scheme 1

Attack of the nucleophilic carbene on the carbonyl carbon, generates an acyl-anion equivalent

(Scheme 1). This nucleophilic species (Breslow Intermediate) inverts the normal reactivity of the

aldehyde. This subsequently promotes nucleophilic attack on an electrophilic species, another

equivalent of benzaldehyde (Scheme 2). The generation of the 1,2 addition product, an -

hydroxyketone, also creates a new stereogenic center.

Scheme 2


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In an effort to generate an asymmetric product by this method, an array of novel chiral

heterazolium carbene precursors have been used with great success. 8-10 Enders et al. were the first to

generate good enantioselectivities for this transformation using their chiral triazolium salt 7 (Figure 3). 8

Figure 3. Examples of chiral triazolium carbene precursors

Besides self condensations, N-heterocyclic carbenes have been used effectively to catalyze cross

condensations between aldehydes and other various electrophiles including aliphatic or aromatic

aldehydes11

, ketones12

, imines13

and even activated double bonds ( Stetter reaction).15

Since its initial discovery in 1976, the Stetter reaction has evolved into one of the most

important procedures for the synthesis of 1,4-dicarbonyl compounds. 15 This transformation consists of a

nucleophile catalyzed conjugate addition of an aldehyde to a Michael accepter such as an enone. The

active catalyst is a thiazolium, imidazolium or triazolium salt, which forms a N-heterocyclic carbene in

situ upon deprotonation (Figure 4). In addition to intermolecular Stetter products, intramolecular 1,4-

additions have the ability to form highly functionalized cyclic products.

Enders and co-workers were the first to report an asymmetric variant of the intramolecular

Stetter reaction using chiral triazolium salts. 16 This facet was later expounded upon most notably by

Rovis et al. , in their design and functional assessment of polycyclic pyrrolidine and aminoindanol-derived


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triazolium salts. 17 He successfully showed in subsequent reports that these catalyst frameworks were

versatile and suitable for a variety of other asymmetric Stetter-type transformations. 18 The

aforementioned catalysts of type 4 and 5 (Figure 3) have proved exceptional in generating some

products in excellent enantioselectivies. The multiple applications of these privileged NHCs has

prompted much investigation in the scientific community and consequently the number of asymmetric

transformations mediated by N-heterocyclic carbenes is growing by the day. 19

1.2 Discovery of a Novel Asymmetric Stetter Cyclization

Our group was initially interested in solving an elusive problem faced by synthetic chemists, the

selective catalysis of triene cyclizations. Conjugated trienes can contain many unique functional groups

and their cyclic derivatives could prove to be useful synthetic intermediates. Inspired by the results by

Rovis involving intramolecular Stetter reactions 17-18 , we hypothesized that a catalytic amount of

chiral NHC could be employed to facilitate an asymmetric triene cyclization provided that the

substrates possessed suitable reactivities.

A preliminary study by Guansai Liu, involving activated triene 2 (Equation 1) showed great

promise in converting the acyclic substrate to the corresponding cyclopentenone 3. This method

employed the use of an aminoindanol-derived triazolium salt 1 as catalyst and generated this unique

product with high enantioselectivity (>97 % ee). The proposed catalytic cycle is shown in Figure 4.


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Figure 4. Proposed Catalytic Cycle. Chiral aminoindanol derived triazolium salt 1, is deprotonated upon addition of base togenerate active carbene species 2 . Nucleophilic attack of carbene on aldehyde generates intermediate 3, followed by protontransfer to form enol 4. Equilibration with breslow intermediate 5 , forms an acyl-anion, which readily undergoes intramolecularattack on the Michael acceptor to form cyclic intermediate 6 . Intermolecular proton transfer yields species 7 , which readilyequilibrates to form 8 , followed by reformation of the carbonyl and release of active catalyst.


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This previously unreported structure contains an enantio-enriched quaternary steriogenic

center and an adjacent conjugated diene, thus can be a useful synthetic intermediate for further

transformations. The immediate synthetic application of this discovery later became apparent after

following a two-step transformation, to deliver enantiopure bicyclic lactone (Equation 2). This bicyclic

moiety can be identified in a variety of biologically active natural products in the ginkgolide family. 20

Figure 5. Structure of ginkgolide B

Terpenelactones such as ginkgolide B (Figure 5) have been established as potent PAF receptor

antagonists. 21 Platelet-activating factor (PAF) is an important factor for inflammation and a mediator of

bronchoconstriction in the body, stressing the value of new synthetic routes towards their structural

analogs. 22 In addition, ginkgolide natural products have been shown to inhibit neurotoxicity of amyloid-

plaques that are responsible for Alzheimers disease. 23 The aforementioned structure 4 is difficult to

access by other means (Equation 2). In addition, the enatio-pure bicyclic allylic halides are versatile

intermediates for further transformations and may prove useful in future drug discovery and natural

product total syntheses.

1.3 Synthesis of Conjugated Trienes

To fully realize the overall scope and relevancy of this reaction discovery, a variety of substrate

trienes with different steric and electronic properties were needed. Ideally the product triene would


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have a formyl group at the 5 -position and a Michael acceptor at the 1 carbon to direct the Stetter

cyclization towards its carbon. It was already known that methyl or ethyl ester would be sufficient to

activate the double bond at that position. 24 The incorporation of aliphatic and aromatic substituents

positioned along the polyene chain must also be tolerated (Figure 6). The route chosen to procure the

desired conjugated trienes was to link them together in a series of coupling reactions.

Since the geometry of the conjugated double bonds could play a significant role in the outcome

of a successful result, the synthetic steps were designed after procedures known to maximize the yield

of select isomers. It was determined that a geometrically defined (2E, 4Z, 6E) hepatriene could be

prepared by Stille coupling of a vinyl stannane and a (2E, 4Z) vinyl iodide, and formerly the vinyl iodide

could be prepared by a Witteg reaction from a (2E) vinyl aldehyde and methyltriphenylphosphonium

iodide (Scheme 3).

Scheme 3

2. SYNTHESIS OF COUPLING SUBSTRATES

2.1 Synthesis of Vinyl Stannanes

The earliest work focused on procuring of a variety of aryl vinyl stannanes with different

electronic properties. When finally coupled to form a conjugated triene, these properties would be used

to tune the reactivity and define the overall scope of the asymmetric cyclization reaction. Both electron


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withdrawing and some moderately donating groups on the aromatic ring were sought after. The starting

material moiety was determined by cost factor as derivatives of cinnamaldehyde. Many of these

compounds were known and a few were commercially available. Those that were not readily available

were synthesized from their corresponding benzaldehyde derivative via Aldol condensation with

acetaldehyde in MeOH and strong base such as KOH (Equation 3).

This procedure was adequate for moderately donating groups 1a , 2a , and 5a (Scheme 4) but

proved too reactive when applied to substrates with strong electron withdrawing capabilities. A

modified procedure was developed to use a slightly weaker base (DBU) and by decreasing the reaction

time period. This proved adequate to furnish the desired products 3a , 4a and 6a in acceptable yields.

Scheme 4

The , -unsaturated aldehydes 1a-6a (Scheme 2) were next converted to their corresponding

vinyl iodide. Dimethylaminopyridine (DMAP) catalyzed a mild vinylic halogenation in aqueous THF. This

procedure proved effective for all the substrates investigated and led to the desired -iodoaldehydes


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1b-6b in moderate yield. A facile acetal protection of compounds 1b-6b via triethylorthoformate in

refluxing EtOH delivered the desired products 1c-6c in excellent yields. All unreported compounds were

fully characterized before use in subsequent steps.

The next step was done concurrently with Jing Huang. Compounds 1c - 6c were lithiated by n-

BuLi to displace iodine, then the corresponding organolithium reagent was used in situ . A solution of

Bu3SnCl was added dropwise to the reaction mixture and stirred overnight at -78oC. Due to their liable

nature vinyl stannanes 1d-6d were not fully purified or characterized, instead the crude coupling

substrates were used directly in the Leibskind modified Stille coupling procedure reported by Xu et al. 26

2.2 Synthesis of Vinyl Iodides

This work focused on procuring of a variety of ethyl ester substituted (2E, 4Z) vinyl iodides with

different steric and electronic properties. When finally coupled to form a conjugated triene, these

functional groups would be used to help tune the reactivity and define the overall scope of the

asymmetric cyclization reaction.

Both aliphatic and aromatic 3- substituted (2E) 4-oxobut-2-enoates, were desired. As Wilkerson,

P. began synthesis aromatic derivatives, work began on an ethyl (2E) 3-ethyl -4-oxobut-2-enoate,

compound 14 .


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For the synthesis of ethyl (2E) 3-ethyl -4-oxobut-2-enoate, compound 14 , a novel procedure had

to be developed. It was hypothesized that ethyl glyoxylate could cross condense with butyraldehyde via

a proline catalyzed Aldol condensation, followed by dehydration to yield the desired vinyl aldehyde. An

initial procedure was developed using a catalytic amount L-proline in DCM at 0 oC that yielded the

desired product in acceptable yield without the need for dehydration. Before this discovery, compound

14 had never been synthesized by this method and although it is reported as a byproduct from another

mechanism (REF), has never been fully characterized until now. Compound 14 was also taken one step

further by reaction with a previously prepared methyltriphenylphosphonium iodide Witteg reagent in

dry THF at -78 oC to furnish the previously unreported compound 15 in moderate yield and good

diastereoselectivity - 10:1/Z:E.

3. RESULTS

The array of novel vinyl stannanes and vinyl iodides were passed on to Guansai Liu, to form

fourteen distinct substrate variants. A Liebeskind modified Stille coupling procedure was adopted that

involved Pd(PPh 3)4 catalyst and CuTC, to join distinct vinyl tin and vinyl iodides together. These

compounds were then de-protected to generate the reactive conjugated trienes in good yield. These

substrates were then successfully applied in the novel asymmetric Stetter cyclization reaction. 26


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4. CONCLUSION

An efficient one step procedure for the synthesis of ( E )-ethyl 3-formylpent-2-enoate from

commercially available starting materials has been developed herein. The absolute configuration was

determined by NOESY 2-D NMR. This procedure has not been fully optimized and may prove useful in

the development of other 3 substituted (E )-ethyl 4-oxobut-2-enoates. These vinyl aldehydes are useful

synthetic intermediates for a variety of transformations. One example used herein, the Stork-Zhao

Witteg Olefination method 25 generated the corresponding ethyl (2E, 4Z)-3-ethyl-5-iodopenta-2, 4-

dienoate in good yield and selectivity. These vinyl iodides may prove useful in cross-coupling reactions

such as Suzuki-Miyaura, Stille, and Heck coupling. A series of novel aromatic vinyl tin compounds were

also synthesized and fully characterized herein. These compounds were successfully applied in a Stille

coupling reaction by Xu et al. to generate conjugated trienes 26 and may prove useful in other Stille type

transformations.

5. EXPERIMENTAL

5.1 General

All solvents used were dehydrated by an SG Water solvent drying system. All reagents were

purchased from Sigma Aldrich and used without further purification unless otherwise noted. Glassware

was either flame dried under vacuum or dried in an oven at 120 oC, assembled hot under a continuous

argon atmosphere and capped with a rubber septum. 1H NMR and 13C NMR spectra were obtained in

CDCl3 at 27 C on a Bruker 400 MHz instrument. Chloroform peaks for1H NMR and 13C NMR spectra

were referenced at 7.27 and 77.0 ppm respectively. All final products were fully characterized by 1H

NMR, 13C NMR, mass spectrometry, and infrared spectroscopy.


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5.2 Synthesis of Vinyl Tin Compounds

General procedure for the preparation of (2E)-(3-phenyl-substituted)-prop-2-enals 1a-6a

To a solution of substituted benzaldehyde (100 mmol) and acetaldehyde (150 mmol) at 0 oC,

KOH (110 mmol) in MeOH (250 mL) was added dropwise via gradutated addition funnel over the course

of several hours. This solution was allowed to warm to RT over 12 h. The solution was quenched by 0.1

M HCl and extracted with DCM. The combined organic layers were dried over Na 2SO4 and the solvent

removed in vacuo . Column chromatography on silica gel (pure DCM) afforded products 1a , 2a and 5a in

moderate (40-55%) yield.

Compounds 3a , 4a and 6a , were prepared as previously described with slight modifications. To a

solution of substituted benzaldehyde (35 mmol) and acetaldehyde (40 mmol) at 0 oC, DBU (70 mmol)

was added dropwise and the solution stirred for 1 h. This solution was allowed to warm to room

temperature over the course of 4 h after which the solution was quenched with 0.1 M HCl and extracted

with DCM. The combined organic layers were dried over Na 2SO4 and the solvent removed in vacuo .

Column chromatography on silica gel (pure DCM) afforded products in (35-40%) yield, all spectra agreed

with reported data.

General procedure for synthesis of (Z)-2-iodo-(phenyl-substituted)acrylaldehydes 1b-6b

Compounds were prepared by dissolving , - unsaturated aldehyde 1a-6a (1 mmol) in a mixture

of THF/H2O (5 mL, 1:1). K 2CO3 (0.17 g, 1.2 mmol), iodine (0.38 g, 1.5 mmol) and DMAP (0.024 g, 0.2

mmol) were added in succession. The reaction mixture was stirred at RT for 24 h, then diluted with DCM


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and washed with saturated Na 2S2O3. The combined organic layers were dried over Na 2SO4, filtered and

the solvent was removed in vacuo . Column chromatography on silica gel (hexanes : DCM = 1:2) afforded

product -iodoaldehydes in (50-70%) yield.

General procedure for acetal protection of -iodoaldehydes 1c-6c

To a solution of (2Z)-2-iodo-(3-phenyl-substituted)-prop-2-enal, 1b-6b (2 mmol) and

triethylorthoformate (0.2 mL, 1.2 mmol) in EtOH (2 mL) was added a catalytic amount of NH 4Cl (4.3 mg,

0.08 mmol). The resultant mixture was stirred under reflux until all the starting material was consumed

as monitored by TLC. The solvent was then removed in vacuo, column chromatography on silica gel

(hexanes : EtOAc : Et 3N = 1 : 4 : 0.2) afforded product in (90-98%) yield.

General procedure for the synthesis of vinyl stannanes 1d-6d

To a flame dried flask was charged vinyl iodide 1c-6c (3 mmol) and Et 2O (35 mL). The resultant

solution was cooled to -78 oC and n-BuLi (2.5 M in hexanes, 1.4 mL, 3.3 mmol) was added dropwise. The

reaction mixture was stirred for 10 min and Bu 3SnCl (0.9 mL, 3.3 mmol) was added dropwise. After

stirring for an additional 2 h at -78 oC, H2O (2 mL) was added to quench the reaction. The organic

solution was washed with H 2O, brine, dried over Na 2SO4, filtered and concentrated in vacuo . Column

chromatography by a short silica gel column (hexanes : Et 3N = 19 : 1) afforded vinyl tin compound that

was found adequate to allow progression to the next step without further purification (83-91%).


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5.2 Synthesis of Vinyl Iodides

General Procedure for the Synthesis of Vinyl Aldehydes via Proline Catalyzed Aldol Condensation

To a solution of butyraldehyde (1 mmol) in dry DCM (10 mL) was added ethyl glyoxylate (50% in

toluene, 2.5 mmol) and L-proline (0.5 mmol). The resultant solution was cooled to 0 oC and DBU (1.1

mmol) was added dropwise. The mixture was stirred for 1 h then allowed to warm to RT and stirred for

an additional 2 h. The organic solution was washed with H 2O and the combined organic layers dried over

Na2SO4 before being concentrated in vacuo . Column chromatography by a short silica gel column

(hexanes : EA = 20 : 1) afforded product 14 in (42%) yield.

General Procedure for the Synthesis of (2E, 4Z) Vinyl Iodides via Stork-Zhao Witteg Olefination 25

To a flame-dried round bottom flask was charged THF (15 mL) and (iodomethyl)

triphenylphosphonium iodide (1.6 g, 3 mmol). NaHMDS (1.0 M in THF, 3.0 mL, 3 mmol) was added

dropwise at RT. After the solid was dissolved, the solution was stirred for an additional 10 min then

cooled to -60o

C. HMPA (3.8 mmol) was added dropwise. The reaction mixture was cooled to -78o

C and

stirred for 15 min. Vinyl aldehyde 14 (2.5 mmol) in THF (10 mL) was added dropwise and the reaction

mixture was allowed to stir for 30 min. Hexanes (50 mL) was added to quench the reaction and the

resultant suspension was filtered through celite. The filtrate was washed by H 2O x 5 (25 mL) and brine.


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The combined organic layers were dried over Na 2SO4, filtered and concentrated in vacuo . Column

chromatography on silica gel (hexanes : EtOAc = 20 : 1) afforded vinyl iodide 15 (Z/E = 10/1) in (55-60%)

yield.

5.4 Compound Characterization

(E)-3-(p-tolyl)acrylaldehyde (1a ): known compound: 1H NMR (400 MHz, CDCl3) ppm 9.71 (d, J

= 7.6 Hz, 1H), 7.46 (d, J = 2.5 Hz, 2H), 7.43 (d, J = 16 Hz, 1H), 7.24 (d, J = 8 Hz, 2H), 6.72 (dd, J = 7.6, 16 Hz,

1H), 2.39 (s, 3H)

(E )-3-(4-methoxyphenyl)acrylaldehyde (2a ): known compound: 1H NMR (400 MHz, CDCl3) ppm 9.64

(d, J = 7.6 Hz, 1H), 7.52 (d, J = 8 Hz, 2H), 7.42 (d, J = 16 Hz, 1H) 6.94 (d, J =8 Hz, 2H), 6.60 (dd, J = 7.6, 16

Hz, 1H) 3.86 (s, 3H)

(E )-3-(3-chlorophenyl)acrylaldehyde (3a ): known compound: 1H NMR (400 MHz, CDCl3) ppm 8.61 (d, J

= 7.5 Hz, 1H), 7.28-7.44 (m, 5H), 6.60 (dd, J = 16, 7.5 Hz, 1H)

(E )-3-(4-bromophenyl)acrylaldehyde (4a ): known compound: 1H NMR (400 MHz, CDCl3) ppm 9.71 (d, J

= 7.5 Hz, 1H), 7.57 (d, J =8.5 Hz, 1H), 7.45 7.40 (m, 3H), 6.70 (dd, J = 16.0, 7.5 Hz, 1H)


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(E )-3-(benzo[d][1,3]dioxol-5-yl)acrylaldehyde (5a ): known compound: 1H NMR (400 MHz, CDCl3) ppm

9.65 (d, J = 7.6 Hz, 1H) 7.38 (d, J = 16.0 Hz, 1H), 7.06-7.08 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.56 (dd, J =

16.0, 7.6 Hz, 1H) 6.05 (s, 2H)

(E )-3-(4-chlorophenyl)acrylaldehyde : known compound: 1H NMR (400 MHz, CDCl3) ppm 9.70 (d, J =

7.6 Hz, 1H), 7.527.40 (m, 5H), 6.6 8 (dd, J = 16.0 Hz, 7.6 Hz, 1H)

( Z )-2-iodo-3-p-tolylacrylaldehyde (1b ): known compound: 1H NMR (400 MHz, CDCl3) p pm 8.76 (s, 1

H), 8.06 (s, 1 H), 8.95 (d, J = 12.0 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H)

( Z )-2-iodo-3-(4-methoxyphenyl)acrylaldehyde (2b ): known compound: 1H NMR (400 MHz, CDCl3) ppm

8.74 (s, 1 H), 8.09 (d, J = 8.0 Hz, 2 H), 8.04 (s, 1 H), 7.02 (d, J = 8.0 Hz, 2 H), 3.89 (s, 3 H)

( Z )-3-(3-chlorophenyl)-2-iodoacrylaldehyde (3b ): 1H NMR (400 MHz, CDCl3) ppm 8.80 (s, 1 H), 8.04 (s,

1 H), 7.99 (s, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.55 7.38 (m, 2 H); 13C NMR (100 MHz, CDCl3): 188.7, 153.9,

135.9, 131.3, 129.9, 128.3, 107.7 ; IR (film) max, 30 65 (w), 2827 (m), 1685 (s), 1587 (m), 1559 (m), 1469


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(m), 1412 (m), 1265 (m), 1204 (m), 1086 (s) cm-1; HRMS (ESI-TOF) for C 9H3O3I [M + H+] calculated

292.9230, found 292.9233

( Z )-3-(4-bromophenyl)-2-iodoacrylaldehyde (4b ): m.p. 105 107 C; 1H NMR (400 MHz, CDCl3) ppm

8.78 (s, 1 H), 8.03 (s, 1 H), 7.88 (d, J = 12.0 Hz, 2 H), 7.63 (d, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3):

188.8, 154.2, 133.0, 132.0, 131.7, 126.1, 106.8; IR (film) max, 2829 (w) , 1674 (s), 1595 (m), 1579 (s),

1557 (m), 1485 (m), 1407 (m), 1278 (m), 1078 (s), 1091 (s) cm-1; HRMS (ESI-TOF) for C 9H7OBrI [M +

H+] calculated 336.8725, found 336.8735

( Z )-3-(benzo[d][1,3]dioxol-5-yl)-2-iodoacrylaldehyde (5b ): 1H NMR (400 MHz, CDCl3) ppm 8.73 (s, 1 H),

7.98 (s, 1 H), 7.85 (s, 1 H), 7.46 (dd, J = 8.0, 4.0 Hz, 2 H), 6.92 (d, J = 8.0 Hz, 2 H), 6.08 (s, 2 H); 13C NMR

(100 MHz, CDCl3): 189.0, 155.2, 150.84, 147.83, 128.07, 128.04, 109.4, 108.6, 102.93, 102.0; IR (film)

max, 2923 (s), 2853 (m), 1679 (s), 1572 (s), 1501 (s), 1486 (s), 1449 (s), 1361 (m), 1314 (w), 1255 (s),

1090 (s), 1035 (s) cm-1; HRMS (ESI-TOF) for C 9H3O3I [M + H+] calculated 302.9518, found 302.9576

( Z )-3-(4-chlorophenyl)-2-iodoacrylaldehyde (6b ): known compound: 1H NMR (400 MHz, CDCl3) ppm

8.81 (s, 1 H), 8.07 (s, 1 H), 7.98 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H)


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( Z )-1-(3,3-diethoxy-2-iodoprop-1-enyl)-4-methylbenzene (1c ): 1H NMR (400 MHz, CDCl3) ppm 7.52 (d,

J = 8.0 Hz, 2 H), 7.27 (d, J = 4.0 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 4.72 (s, 1 H), 3.70 3.56 (m, 4 H), 2.36 (s,

3 H), 1.29 (t, J = 8.0 Hz, 6 H); 13C NMR (100 MHz, CDCl3): 138.4, 136.2, 133.6, 128.80, 128.76, 105.1,

103.8, 61.9, 21.4, 15.1; IR (film) max, 3057 (w), 2975 (m), 2928 (w) , 2878 (m), 1480 (w), 1445 (m), 1329

(m), 1116 (s), 1055 (s) cm-1; HRMS (ESI-TOF) for C 14H19O2INa [M + Na+] calculated 369.0328, found

369.0313

( Z )-1-(3,3-diethoxy-2-iodoprop-1-enyl)-4-methoxybenzene (2c ): 1H NMR (400 MHz, CDCl3) ppm 7.64

(d, J = 12.0 Hz, 2 H), 6.92 (d, J = 8.0 Hz, 1 H), 4.71 (s, 1 H), 3.84 (s, 3 H), 3.71 3.57 (m, 4 H), 1.30 (t, J = 8.0

Hz, 6 H); 13C NMR (100 MHz, CDCl3): 159.7, 135.7, 130.4, 128.0, 113.4, 105.2, 102.4, 61.9, 55.2, 15.1; IR

(film) max, 2829 (w ), 1674 (s), 1595 (m), 1579 (s), 1557 (m), 1485 (m), 1407 (m), 1278 (m), 1078 (s),

1091 (s) cm-1; HRMS (ESI-TOF) for C 14H19O3INa [M + Na+] calculated 385.0277, found 385.0267

( Z )-1-chloro-3-(3,3-diethoxy-2-iodoprop-1-enyl)benzene (3c ): 1H NMR (400 MHz, CDCl3) ppm 7.58 (s, 1

H), 7.48 7.46 (m, 1 H), 7.33 7.28 (m, 3 H), 4.79 (s, 1 H), 3.73 3.58 (m, 4 H), 1.31 (t, J = 7.2 Hz, 6 H); 13C

NMR (100 MHz, CDCl3): 138.7, 135.1, 129.4, 128.8, 128.3, 127.0, 106.5, 104.8, 62.0, 15.1; IR (film) max,

2976 (m), 2919 (m), 1593 (w), 1564 (w), 1473 (m), 1119 (s), 1061 (s) cm-1; HRMS (ESI-TOF) for

C13H16O2ClINa [M + Na+] calculated 388.9781, found 388.9772


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( Z )-1-bromo-4-(3,3-diethoxy-2-iodoprop-1-enyl)benzene (4c ): 1H NMR (400 MHz, CDCl3) ppm 7.51

7.45 (m, 4 H), 7.24 (s, 1 H), 4.75 (s, 1H), 3.72 3.54 (m, 4 H), 1.28 (t, J = 8.0 Hz, 6 H); 13C NMR (100 MHz,

CDCl3): 135.6, 135.2, 131.3, 130.4, 9 122.4, 105.7, 104.8, 62.0, 15.1; IR (film) max, 2974 (m), 2928 ( w)

2878 (m), 1485 (m), 1396 (m), 1329 (m), 1115 (s), 1048 (s), 1009 (s) cm-1; HRMS (ESI-TOF) for

C13H16O2BrINa [M + Na+] calculated 432.9276, found 432.9266

( Z )-5-(3,3-diethoxy-2-iodoprop-1-enyl)benzo[d][1,3]dioxole (5c ): 1H NMR (400 MHz, CDCl3) ppm 7.28

(s, 1 H), 7.20 (s, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 1 H), 5.99 (s, 1 H), 4.70 (s, 1 H), 3.69

3.54 (m, 4 H), 1.28 (t, J = 8.0 Hz, 6 H); 13C NMR (100 MHz, CDCl3): 146.3, 135.7, 123.7, 108.7, 108.0,

105.2, 103.1, 101.2, 61.9, 15.1; IR (film) max, 2977 (m), 2888 (m), 2247 (w), 1605 (w), 1504 (m), 1489

(s), 1445 (m), 1259 (m), 1117 (m), 1059 (s), 1041 (s) cm-1; HRMS (ESI-TOF) for C 14H17O4INa [M + Na+]

calculated 399.0069, found 399.0061

( Z )-1-chloro-4-(3,3-diethoxy-2-iodoprop-1-enyl)benzene (6c ): 1H NMR (400 MHz, CDCl3) ppm 7.55 (d, J

= 8.8 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.29 (s, 1 H), 4.78 (s, 1 H), 3.74 3.56 (m, 4 H), 1.31 (t, J = 7.2 Hz, 6


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H); 13C NMR (100 MHz, CDCl3): 135.16, 135.15, 134.17, 130.2, 128.3, 105.7 104.9, 62.0, 15.1 ; IR (film)

max, 2976 (m), 2928 (w), 2879 (m), 1593 (m), 1564 (m), 1473 (m), 1409 (w), 1333 (w), 1257 (w), 1116

(s), 1055 (s) cm-1; HRMS (ESI-TOF) for C 13H16O2ClINa [M + Na+] calculated 388.9781, found 388.9777

ethyl (2E)-formylpent-2-enoate (14 ): 1H NMR (400 MHz, CDCl3) 9.52 (s, 1H), 6.44 (s, 1H), 4.31-

4.26 (q, J = 7 Hz, 2H), 2.73-2.67 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.05 (t, J = 8 Hz, 3H); 13C NMR

(100 MHz, CDCL3): 194.34, 165.24, 155.8, 135.2, 61.05, 18.3, 14.1, 13.15; HRMS (ESI-TOF) for C 8H13O3[M

+ H+] calculated 157.0865, found 157.0863

ethyl (2E, 4Z)-3-ethyl-5-iodopenta-2, 4-dienoate (15 )( Z/E = 10/1): 1H NMR (400 MHz, CDCl3) ppm 6.73

(d, J = 8.8 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H) 5.98 (s, 1H), 4.23-4.18 (q, J = 7.1 Hz, 2H), 2.81-2.75 (q, J = 7.6

Hz, 2H), 1.31 (t, J = 7.24 Hz, 3H), 1.09 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCL3): 166.0, 157.65, 140.1,

119.1, 82.64, 60.0, 24.34, 14.25, 12.73; HRMS (ESI-TOF) for C 9H14O2I [M + H+] calculated 281.0039, found

281.0029


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Synthesis of Coupling Substrates for Use in a Highly Enantioselec

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Transcript of Synthesis of Coupling Substrates for Use in a Highly Enantioselec